1. Field of the Invention
The present invention relates to reconstituted surfactants comprising a lipid carrier, and a combination of (i) a polypeptide analog of the native surfactant protein SP-C and (ii) a polypeptide comprising a sequence comprised of repeated units where each unit contains between 3 and 8 hydrophobic amino acid residues and one basic amino acid residue. The present invention also relates to pharmaceutical compositions thereof for use in the prophylaxis and/or treatment of RDS and other respiratory disorders.
2. Discussion of the Background
The human lung is composed of a large number of small air sacs, called alveoli, in which gases are exchanged between the blood and the air spaces of the lungs. In healthy individuals, this exchange is mediated by the presence of a protein-containing surfactant complex that prevents the lungs from collapsing at the end of expiration.
The lung surfactant complex is primarily composed of lipids and contains minor amounts of various proteins. When the level of this complex becomes inadequate levels the lung will not function properly. This syndrome is called Respiratory Distress Syndrome (RDS). RDS commonly affects preterm infants.
Heretofore, RDS has been effectively treated with modified natural surfactant preparations extracted from animal lungs. Commercially available modified surfactant preparations include: (i) Curosurf, derived from porcine lung, (ii) Infasurf, extracted from calf lung lavage and (iii) Survanta, a chemically modified natural bovine lung extract.
The main constituents of the commercially available surfactant preparations are phospholipids, such as 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, commonly known as dipalmitoylphosphatidylcholine (DPPC); phosphatidylglycerol (PG); and surfactant hydrophobic proteins B and C (SP-B and SP-C).
There are some significant drawbacks in using surfactant preparations from animal tissues. These drawbacks include difficulties arising during complex production and the sterilization process. Further drawbacks include the possible induction of immune reactions. Accordingly, synthetic surfactants mimicking the composition of the modified natural surfactants have been developed. Synthetic surfactants are known as reconstituted surfactants.
The development of clinically active reconstituted surfactants has turned out to be complicated since the native hydrophobic proteins are too big to synthesize, structurally complex and unstable in pure form. In order to replace native hydrophobic proteins, some synthetic polypeptides partially corresponding to their sequences and analogs thereof have been proposed, for example, in WO 89/06657, WO 92/22315, WO 95/32992, U.S. Pat. No. 6,660,833, EP 413,957, WO 91/18015 and WO 00/47623.
In these references, the treatment with reconstituted surfactants in animal studies gives rise to poor lung gas volumes and grade of alveolar patency at the end of expiration. Thus, ventilation is required with a positive end expiratory pressure (PEEP) in order to achieve an in vivo activity comparable to that achieved with modified natural surfactants (Johansson J et al J Appl Physiol 2003, 95, 2055-2063; Davis A J et al Am J Respir Crit Care Med 1998; 157, 553-559).
The reconstituted surfactant preparations available heretofore are indeed not sufficient to form a stable phospholipid film in the alveoli at the end of expiration. As such, there remains an unmet need for a reconstituted surfactant with improved properties in terms of lung compliance. In particular there is a need for a reconstituted surfactant preparation which is able to guarantee alveolar stability, and hence to maintain alveolar stability at the end of expiration without requiring ventilation with PEEP.